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1.
Georgian Med News ; (327): 36-41, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35959931

ABSTRACT

The problem of analysis of clinical - diagnostic and biochemical criteria of postoperative cognitive dysfunction in abdominal oncosurgery, depending on the degree and structure of disorders, remains unresolved, which determines its relevance. The role of 2, 3-diphosphoglycerate is essential, because its increase in the concentration of red blood cells in hypoxic conditions is one of the adaptive mechanisms that improve oxygen transport to tissues. Purpose. The influence of the dynamics of 2,3 diphosphoglycerate content, as the main indicator of hypoxia, on the occurrence of cognitive dysfunction in the postoperative period in patients with neoplasms of the abdominal cavity. The study was conducted on the basis of departments for patients of the surgical profile of the municipal institution "Kharkiv City Clinical Hospital of Ambulance and Emergency Care named after Professor OI Meshchaninov ". To achieve this goal, we examined 80 patients with abdominal neoplasms who underwent surgery under general anesthesia using propofol and fentanyl. All patients were divided into 2 groups depending on the age of patients on the WHO scale, who underwent surgery using general anesthesia: Group 1 (n = 39) - middle-aged patients (50-59 years); Group 2 (n = 41) - elderly and senile patients (60-80 years). The control points of the examination were the day before the operation and the 1st, 7th, 30th day from the moment of the operation. The state of cognitive function in these patients was determined by conducting neuropsychological tests. To assess the state of cognitive function of patients, neuropsychological tests were used: MMSE scale (Mini-Mental State Examination, MMSE), the method of memorizing 10 words AR Luria, frontal dysfunction battery (FAB), Schulte technique. To assess the state of energy metabolism in patients, the level of erythrocytes and hemoglobin in the blood analysis was determined by well-known methods, the level of 2,3 diphosphoglycerate in erythrocytes and its ratio to hemoglobin. Anemia in the first week after surgery in patients of group 1 contributes to the development of a hypoxic state, in erythrocytes there is an increase in the content of 2,3 41 diphosphoglycerate, which promotes the transport of oxygen to tissues. During the week there is an increase in the intensity of the formation of 2,3 diphosphoglycerate, as evidenced by the ratio of 2,3 diphosphoglycerate to hemoglobin. In patients of group 2, the changes are more pronounced: anemia with a significant decrease in erythrocytes and hemoglobin in the blood, a decrease in 2.3 diphosphoglycerate in erythrocytes, reflects changes in erythrocyte metabolism, namely a decrease in biosynthesis of important organophosphorus compounds, in particular 2,3 diphosphogly by reducing the basic enzymes of glycolysis. Decreased energy metabolism in the elderly contributes to impaired cell function. With age, the content of adenosine triphosphate, 2,3 diphosphoglycerate decreases, thus increasing the affinity of hemoglobin for oxygen, impaired transport of oxygen to tissues, which leads to the development of hypoxia. According to the results of neuropsychological tests, we found postoperative cognitive dysfunction in patients with neoplasms of the abdominal cavity. Disruption of energy metabolism and changes in the activity of glycolysis enzymes in erythrocytes contributes to a decrease in the concentration of 2, 3 diphosphoglycerate, increase the affinity of hemoglobin for oxygen and the development of tissue hypoxia. The obtained results indicate the interdependence of these processes and allow continuing research in this direction with the development of appropriate clinical and diagnostic measures and areas of intensive care to improve the condition of patients with abdominal tumors and their quality of life after surgery.


Subject(s)
Abdominal Neoplasms , Anemia , Cognitive Dysfunction , Postoperative Cognitive Complications , 2,3-Diphosphoglycerate/metabolism , Abdominal Neoplasms/complications , Abdominal Neoplasms/metabolism , Abdominal Neoplasms/surgery , Aged , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Diphosphoglyceric Acids/metabolism , Erythrocytes/metabolism , Hemoglobins , Humans , Hypoxia , Middle Aged , Oxygen/metabolism , Postoperative Period , Quality of Life
2.
Cancer Metastasis Rev ; 38(4): 783-811, 2019 12.
Article in English | MEDLINE | ID: mdl-31848768

ABSTRACT

Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.


Subject(s)
Abdominal Neoplasms/genetics , MicroRNAs/genetics , Abdominal Neoplasms/metabolism , Animals , Child , Humans , MicroRNAs/biosynthesis
3.
Methods ; 121-122: 138-145, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28522325

ABSTRACT

Recurrent chromosomal translocations often lead to expression of fusion proteins associated with oncogenic transformation. To study translocations and downstream events, genome editing techniques have been developed to generate chromosomal translocations through non-homologous end joining of DNA double-strand breaks introduced at the two participating endogenous loci. However, the frequencies at which these events occur is usually too low to efficiently clone cells carrying the translocation. This article provides a detailed method using CRISPR-Cas9 technology and homology-directed repair to efficiently isolate cells harboring a chromosomal translocation. For an additional level of control, the resulting fusion protein is conditionally expressed to allow early events in oncogenic transformation to be studied. We focus on the generation of the EWSR1-WT1 fusion using human mesenchymal cells, which is associated with the translocation found in desmoplastic small round cell tumors.


Subject(s)
Abdominal Neoplasms/genetics , Bacterial Proteins/genetics , CRISPR-Cas Systems , Clustered Regularly Interspaced Short Palindromic Repeats , Desmoplastic Small Round Cell Tumor/genetics , Endonucleases/genetics , RNA, Guide, Kinetoplastida/genetics , Abdominal Neoplasms/metabolism , Abdominal Neoplasms/pathology , Bacterial Proteins/metabolism , CRISPR-Associated Protein 9 , Cell Line , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 22 , DNA Breaks, Double-Stranded , Desmoplastic Small Round Cell Tumor/metabolism , Desmoplastic Small Round Cell Tumor/pathology , Endonucleases/metabolism , Genome, Human , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Mutagenesis, Site-Directed/methods , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , RNA, Guide, Kinetoplastida/metabolism , RNA-Binding Protein EWS/genetics , RNA-Binding Protein EWS/metabolism , Recombinational DNA Repair , Translocation, Genetic , WT1 Proteins/genetics , WT1 Proteins/metabolism
4.
Blood ; 121(13): 2563-6, 2013 Mar 28.
Article in English | MEDLINE | ID: mdl-23361906

ABSTRACT

Hypoxia-inducible factors (HIFs) control the cellular response to hypoxia and, when dysregulated, contribute to tumorigenesis. Previously, we identified 2 gain-of-function somatic mutations in patients presenting with multiple paragangliomas or somatostatinomas, and polycythemia. Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, leading to stabilization of HIF-2α and increased expression of hypoxia-related genes.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Mutation , Oxygen/metabolism , Pancreatic Neoplasms/genetics , Paraganglioma/genetics , Polycythemia/genetics , Somatostatinoma/genetics , Abdominal Neoplasms/genetics , Abdominal Neoplasms/metabolism , Amino Acid Sequence , Base Sequence , Basic Helix-Loop-Helix Transcription Factors/chemistry , Basic Helix-Loop-Helix Transcription Factors/metabolism , Child , Child, Preschool , Female , HeLa Cells , Humans , Models, Molecular , Molecular Sequence Data , Mutation/physiology , Pancreatic Neoplasms/metabolism , Paraganglioma/metabolism , Phylogeny , Polycythemia/metabolism , Somatostatinoma/metabolism
5.
Pediatr Blood Cancer ; 62(5): 897-900, 2015 May.
Article in English | MEDLINE | ID: mdl-25663425

ABSTRACT

We report on how MLPA and Sequencing of SMARCB1/INI1/SNF5 might be applied for initial diagnosis of rhabdoid tumor patients. These techniques were successfully used to detect loss of SMARCB1 in tumor cells of the ascites in a 3-month-old patient in which tumor biopsy could not initially be made due to life threatening intraabdominal bleedings.


Subject(s)
Abdominal Neoplasms/diagnosis , Ascites/pathology , Biomarkers, Tumor/metabolism , Chromosomal Proteins, Non-Histone/metabolism , DNA-Binding Proteins/metabolism , Rhabdoid Tumor/diagnosis , Transcription Factors/metabolism , Abdominal Neoplasms/genetics , Abdominal Neoplasms/metabolism , Ascites/genetics , Ascites/metabolism , Biomarkers, Tumor/genetics , Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Female , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Infant , Nucleic Acid Amplification Techniques , Polymerase Chain Reaction , Prognosis , Rhabdoid Tumor/genetics , Rhabdoid Tumor/metabolism , SMARCB1 Protein , Transcription Factors/genetics
6.
Pediatr Hematol Oncol ; 32(1): 60-9, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25264623

ABSTRACT

Desmoid fibromatosis is a benign fibroblastic neoplasm with high recurrence rates predominantly observed in pediatric and adolescent patients. The use of wide resection margins has been discussed controversially in literature. In addition, data on non-surgical treatment is limited as phase III studies are still missing. Nineteen patients under the age of 18 years were identified. Tumor location, surgical treatment for primary or recurrent tumors, resection margins, medical neo-/adjuvant treatment, time to recurrence as well as immunohistochemical markers (estrogen receptor, ER α and ß, progesterone and androgen receptors, somatostatin, Ki-67, c-kit, platelet-derived growth factor receptors, PDGFRs, α and ß, ß-catenin) were evaluated. The mean age at diagnosis was 6.6 years, with a mean follow-up of 114 months. Recurrences were detected in four out of nineteen patients. Surprisingly, the recurrence rate was not influenced by type of resection used (R0, R1/2). All samples were tested negative for ER α, somatostatin, and progesterone receptor. In contrast, a majority of tumors showed positive results for PDGFR α and ß and ß-catenin. No correlation between positive immunohistochemical markers and tumor recurrences was detectable. In conclusion, recurrence rates are not depending on resection type and immunohistochemical markers seem to behave differently in children and adolescents in contrast to adult patients.


Subject(s)
Abdominal Neoplasms , Adenomatous Polyposis Coli , Biomarkers, Tumor/metabolism , Fibromatosis, Aggressive , Neoplasm Recurrence, Local , Abdominal Neoplasms/metabolism , Abdominal Neoplasms/pathology , Abdominal Neoplasms/surgery , Adenomatous Polyposis Coli/metabolism , Adenomatous Polyposis Coli/pathology , Adenomatous Polyposis Coli/surgery , Adolescent , Adult , Child , Child, Preschool , Female , Fibromatosis, Aggressive/metabolism , Fibromatosis, Aggressive/pathology , Fibromatosis, Aggressive/surgery , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Retrospective Studies
7.
Dev Neurosci ; 36(5): 422-31, 2014.
Article in English | MEDLINE | ID: mdl-25171250

ABSTRACT

Neuroblastoma is a childhood cancer caused by the transformation of sympathoadrenal progenitors. By following the formation of tumors in homozygous TH-MYCN mice, an established mouse model of neuroblastoma, we were able to capture transformed cells prior to the formation of large, vascularized tumors in order to determine the responsiveness of cells to neurotrophic factors. We discovered that the ciliary neurotrophic factor (CNTF) receptor is abundantly expressed in tumor cells from these mice. Furthermore, CNTF - but not nerve growth factor, brain-derived nerve growth factor, neurotrophin 3, or glial cell line-derived neurotrophic factor - promoted neuronal differentiation and withdrawal from the cell cycle. Thus, the transformation of sympathoadrenal progenitors by MYCN overexpression differentially affects responsiveness to neurotrophic molecules.


Subject(s)
Abdominal Neoplasms/drug therapy , Cell Differentiation/drug effects , Ciliary Neurotrophic Factor/pharmacology , Neuroblastoma/drug therapy , Receptor, Ciliary Neurotrophic Factor/metabolism , Abdominal Neoplasms/metabolism , Animals , Cell Proliferation/drug effects , Ciliary Neurotrophic Factor/therapeutic use , Disease Models, Animal , Mice , Neuroblastoma/metabolism , Neurons/drug effects , Neurons/metabolism , Receptor, Ciliary Neurotrophic Factor/genetics
8.
Part Fibre Toxicol ; 11: 59, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25410479

ABSTRACT

BACKGROUND: Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods. METHODS: A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 109 or 5 × 109 WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (108 WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans. RESULTS: Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D - the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis. CONCLUSION: We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.


Subject(s)
Abdominal Neoplasms/chemically induced , Carcinogens/toxicity , Mesothelioma/chemically induced , Nanotubes, Carbon/toxicity , Abdominal Neoplasms/metabolism , Abdominal Neoplasms/pathology , Animals , Carcinogenicity Tests , Carcinogens/administration & dosage , Carcinogens/chemistry , Dose-Response Relationship, Drug , Immunohistochemistry , Injections, Intraperitoneal , Male , Mesothelioma/metabolism , Mesothelioma/pathology , Microscopy, Electron, Scanning , Nanotubes, Carbon/chemistry , Nanotubes, Carbon/ultrastructure , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Particle Size , Rats, Wistar , Serous Membrane , Survival Analysis
9.
World J Surg Oncol ; 12: 9, 2014 Jan 10.
Article in English | MEDLINE | ID: mdl-24410799

ABSTRACT

Desmoplastic small round cell tumor is a rare malignant tumor that has a poor prognosis. It affects predominantly young males. In the current report, a 14-year-old male patient was admitted to the hospital for evaluation of abdominal distension, and abdominal pain. Imaging examination revealed a high prevalence of multiple intraperitoneal and liver parenchymal cystic and solid tumors. After an explorative surgery, the pathological findings confirmed the presentation of desmoplastic small round cell tumor. Diagnosis of desmoplastic small round cell tumor could easily have been overlooked since there was no specific evidence for this condition available in the clinical and imaging examinations. In the present study, ultrasound examination detected solid cystic masses, which suggested the presence of necrosis and hemorrhage. Immunohistochemistry and cytogenetic studies confirmed the diagnosis of desmoplastic small round cell tumor in this patient.


Subject(s)
Abdominal Neoplasms/pathology , Biomarkers, Tumor/metabolism , Desmoplastic Small Round Cell Tumor/pathology , Abdominal Neoplasms/metabolism , Adolescent , Desmoplastic Small Round Cell Tumor/metabolism , Humans , Immunoenzyme Techniques , Male , Prognosis
10.
Histopathology ; 62(2): 287-93, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23020289

ABSTRACT

AIMS: Occasional cases of well-differentiated and dedifferentiated liposarcoma (LPS) contain myxoid stroma, leading to confusion with other sarcomas. The aim of this study was to analyse the clinicopathological and genetic features of well-differentiated/dedifferentiated LPS with prominent myxoid stroma. METHODS AND RESULTS: Fifty-six cases of LPS (22 well-differentiated; 34 dedifferentiated) with prominent myxoid stroma were evaluated. Most arose in the retroperitoneum, abdominal cavity, or spermatic cord. The mean size was 170 mm. Myxoid LPS-like plexiform vessels were conspicuous in 11 cases of well-differentiated LPS. In 22 cases of dedifferentiated LPS, myxofibrosarcoma-like curvilinear vessels were prominent. In other cases, the myxoid component had variably bland or pleomorphic morphology. By immunohistochemistry, staining for MDM2 was positive in 95% of cases, and CDK4 in 78%. Cytogenetics in 13 cases showed ring and giant marker chromosomes. Fluorescence in-situ hybridization showed amplification of 12q13-15 in six cases evaluated. Of 30 patients with follow-up, all but one had local recurrences (up to four), but only one has so far had distant metastases. CONCLUSIONS: Well-differentiated/dedifferentiated LPS with prominent myxoid stroma can closely resemble other sarcoma types, especially myxoid LPS and myxofibrosarcoma. The clinical presentation (large retroperitoneal or abdominal tumour) is a clue to the correct diagnosis; the degree of nuclear atypia helps to exclude myxoid LPS. Immunohistochemistry for MDM2 and CDK4 and genetic analysis can be useful to confirm the diagnosis.


Subject(s)
Abdominal Neoplasms/pathology , Liposarcoma, Myxoid/pathology , Soft Tissue Neoplasms/pathology , Stromal Cells/pathology , Abdominal Neoplasms/genetics , Abdominal Neoplasms/metabolism , Adipocytes/metabolism , Adipocytes/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Chromosome Aberrations , Chromosomes, Human, Pair 12 , Cyclin-Dependent Kinase 4/metabolism , DNA, Neoplasm/analysis , Female , Gene Amplification , Humans , In Situ Hybridization, Fluorescence , Liposarcoma, Myxoid/genetics , Liposarcoma, Myxoid/metabolism , Male , Middle Aged , Mucins/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Retroperitoneal Space , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/metabolism , Stromal Cells/metabolism , Young Adult
12.
Radiographics ; 33(3): 681-702, 2013 May.
Article in English | MEDLINE | ID: mdl-23674769

ABSTRACT

One application of the unique capability of magnetic resonance (MR) imaging for characterizing soft tissues is in the specific detection of lipid. Adipose tissue may be abundant in the body, but its presence in a lesion can greatly limit differential diagnostic considerations. This article reviews MR imaging fat detection techniques and discusses lesions in the abdomen and pelvis that can be readily diagnosed by using these techniques. Traditional fat detection methods include inversion-recovery and chemically selective fat-suppression pulse sequences, with the former being less sensitive to field heterogeneity and less tissue specific than the latter. Chemical shift-based sequences, which exploit the inherent resonance frequency difference between lipid and water to depict intracytoplasmic fat, have great utility for evaluating hepatic steatosis and lesions such as adrenal and hepatic adenomas, hepatocellular carcinoma, focal lipomatosis of the pancreas, and adrenal cortical carcinoma. The signal from large amounts of fat can be suppressed by using a narrow radiofrequency pulse for selective excitation of fat protons (ie, fat saturation imaging), a technique that increases image contrast resolution and highlights lesions such as contrast-enhancing tissue, edema, and blood products. This technique is especially useful for evaluating renal angiomyolipomas, adrenal myelolipomas, ovarian teratomas, and liposarcomas. MR spectroscopy is a promising method for quantifying absolute liver fat concentration and changes in hepatic triglyceride content during treatment. New and evolving techniques include magnetization transfer and modified Dixon sequences. A solid understanding of these techniques will help improve the interpretation of abdominal and pelvic imaging studies.


Subject(s)
Abdominal Neoplasms/metabolism , Abdominal Neoplasms/pathology , Adipose Tissue/metabolism , Lipids/analysis , Magnetic Resonance Imaging/methods , Pelvic Neoplasms/metabolism , Pelvic Neoplasms/pathology , Adipose Tissue/pathology , Humans , Magnetic Resonance Spectroscopy/methods , Molecular Imaging/methods
13.
Cir Pediatr ; 26(3): 112-8, 2013 Jul.
Article in Spanish | MEDLINE | ID: mdl-24482902

ABSTRACT

INTRODUCTION: The existence of cancer stem cells (CSC) in neuroblastoma (NB) has been associated with the development of metastasis, resistance to chemotherapy and recurrence. Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples, and to correlate this expression with clinical variables such as histology, genetics and response to conventional therapy. MATERIAL AND METHODS: We performed a retrospective-experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010-2012 in our Hospital. Fluorescence immunohistochemistry was used to analyze the expression of the different markers: CD44, CD74, CD133, tyrosine hydroxylase, endothelin receptors type A (ETA) and B (ETB), p75, nestina y and Phox2b, all of them related to neural stem cell biology. The level of expression of the markers was then correlated with clinical variables. RESULTS: Nestin expression was positive in 72.2% of samples and ETA in 66.7%. PHOX2B and CD74 expression were lower, being positive in less than 30%. The markers CD44, ETB and PHOX2B were expressed in more aggressive tumors. ETA expression correlated significantly with unfavorable histology tumors (p= 0.01), N-myc amplification (p= 0.05) and recurrence/progression (p= 0.05). CONCLUSION: The expression of CD44, ETB and ETA was associated with more aggressive tumors and poor prognostic factors. These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets.


Subject(s)
Abdominal Neoplasms/metabolism , Biomarkers, Tumor/biosynthesis , Neural Stem Cells/metabolism , Neuroblastoma/metabolism , Child , Humans , Prognosis , Retrospective Studies
14.
Oncologist ; 17(4): 512, 2012.
Article in English | MEDLINE | ID: mdl-22416063

ABSTRACT

BACKGROUND: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. METHODS: CBT-1® was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. (99m)Tc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC(0-3)) was determined for (99m)Tc-sestamibi. RESULTS: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%-100% lower (p < .0001) with CBT-1®. Among 10 patients who completed imaging, the (99m)Tc-sestamibi AUC(0-3) for liver (normalized to the AUC(0-3) of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1® administration. Lung uptake was not changed. CONCLUSION: CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1® to evaluate its ability to modulate drug uptake in tumor tissue. DISCUSSION: Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1(-/-); p53(-/-) mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Abdominal Neoplasms/drug therapy , Abdominal Neoplasms/metabolism , Alkaloids/pharmacology , Antineoplastic Agents/pharmacokinetics , Paclitaxel/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Aged , Antineoplastic Agents/pharmacology , Drug Interactions , Female , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Liver/drug effects , Liver/metabolism , Male , Middle Aged , Paclitaxel/pharmacology , Radiopharmaceuticals/pharmacokinetics , Rhodamine 123/pharmacokinetics , Technetium Tc 99m Sestamibi/pharmacokinetics
15.
World J Surg Oncol ; 10: 98, 2012 May 30.
Article in English | MEDLINE | ID: mdl-22647077

ABSTRACT

BACKGROUND: Cases with subcutaneous metastasis of differentiated hepatocellular carcinoma to the abdominal wall without prior seeding as a consequence of local interventions with a negative or normal alpha-fetoprotein level in the serum are extremely rare. CASE REPORT: This is the first report of a case with AFP-negative, differentiated hepatocellular carcinoma metastasis to the abdominal wall within a pre-existing subcutaneous lipoma since childhood after antiandrogen therapy with leuprorelin and buserelin acetate for prostate cancer without seeding. METHODS: Clinical features including histology, immunohistochemistry, clinical course and surgical approach are presented. RESULTS: Histological examination revealed a hepatocellular carcinoma with a trabecular and pseudoglandular growth pattern with moderately atypical hepatocytes with multifocal bile formation within a lipoma. The postoperative course of abdominal wall reconstruction with a monocryl-prolene mesh and a local flap after potentially curative resection was uncomplicated. DISCUSSION AND CONCLUSION: It may be that previous antiandrogen treatment for prostate carcinoma contributed to the fact that our patient developed alpha-fetoprotein-negative and androgen receptor-negative subcutaneous abdominal wall metastasis within a pre-existing lipoma since childhood.


Subject(s)
Abdominal Neoplasms/secondary , Abdominal Wall/pathology , Androgen Antagonists/adverse effects , Carcinoma, Hepatocellular/pathology , Cell Differentiation , Lipoma/chemically induced , Liver Neoplasms/pathology , alpha-Fetoproteins/metabolism , Abdominal Neoplasms/chemically induced , Abdominal Neoplasms/metabolism , Abdominal Neoplasms/surgery , Abdominal Wall/surgery , Aged , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/surgery , Child , Humans , Lipoma/pathology , Lipoma/surgery , Liver Neoplasms/chemically induced , Liver Neoplasms/metabolism , Liver Neoplasms/surgery , Male , Neoplasm Staging , Prognosis , Prostatic Neoplasms/drug therapy
16.
Pediatr Radiol ; 42(10): 1259-62, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22618629

ABSTRACT

A 3-month-old boy with a history of an abdominopelvic neuroblastoma presented 1 week after tumor resection for a routine follow-up 123-I Meta-iodobenzylguanidine (MIBG) scan to assess for residual mass. The study demonstrated abnormal radiotracer uptake in the right upper lobe, which correlated on the SPECT/CT to an area of airspace consolidation thought to be secondary to atelectasis. To the best of our knowledge, there is one published case of MIBG radiotracer uptake in the lung correlating with pneumonia; however, there are no reported cases to date in the literature of focal pulmonary MIBG uptake corresponding to atelectasis.


Subject(s)
3-Iodobenzylguanidine , Abdominal Neoplasms/complications , Abdominal Neoplasms/diagnostic imaging , Neuroblastoma/diagnostic imaging , Pulmonary Atelectasis/diagnostic imaging , Radiopharmaceuticals , 3-Iodobenzylguanidine/pharmacokinetics , Abdominal Neoplasms/metabolism , Humans , Incidental Findings , Infant , Male , Neuroblastoma/complications , Neuroblastoma/metabolism , Pulmonary Atelectasis/complications , Pulmonary Atelectasis/metabolism , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics
17.
Acta Cytol ; 56(5): 576-80, 2012.
Article in English | MEDLINE | ID: mdl-23075903

ABSTRACT

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a distinctive clinicopathologic entity with an aggressive clinical course that typically involves the abdominal and/or pelvic peritoneum of young males. A population of small round blue cells and a fibroesclerotic stroma are the usual morphologic features. This tumor is characterized by a typical polyphenotypic profile with expression of epithelial, mesenchymal and neural markers. Cytogenetically, this tumor presents a unique abnormality - t(11;22)(p13;q12). CASE: A 29-year-old male without significant medical history was admitted to our institution with gastrointestinal symptomatology. The physical examination and medical imaging studies revealed an extensive soft tissue mass filling the entire peritoneal cavity/pelvis. A fine-needle aspiration (FNA) of the abdominal mass was performed. The FNA smears revealed fragments of collagenous desmoplastic stroma and clusters of loosely cohesive small round cells that showed positivity for epithelial and myogenic markers. Cytogenetic analysis demonstrated rearrangement of the genes EWSR1 and WT1, resulting from the t(11;22)(p13;q12). CONCLUSION: DSRCT is an uncommon neoplasm that shares clinical and cytomorphologic features with other small round cell tumors. Therefore, a primary definitive diagnosis based on cytology specimens may be difficult but plausible and can be aided by a typical clinical presentation and ancillary immunocytochemical/cytogenetic studies.


Subject(s)
Abdominal Cavity/pathology , Abdominal Neoplasms/pathology , Biopsy, Fine-Needle/methods , Desmoplastic Small Round Cell Tumor/pathology , Abdominal Neoplasms/genetics , Abdominal Neoplasms/metabolism , Adult , Biomarkers/analysis , Calmodulin-Binding Proteins/genetics , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 22/genetics , Desmoplastic Small Round Cell Tumor/genetics , Desmoplastic Small Round Cell Tumor/metabolism , Diagnosis, Differential , Fatal Outcome , Gene Rearrangement , Humans , Immunohistochemistry , Keratins/analysis , Male , RNA-Binding Protein EWS , RNA-Binding Proteins/genetics , Translocation, Genetic , Vimentin/analysis , WT1 Proteins/genetics
18.
Int J Surg Pathol ; 30(1): 68-71, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33988473

ABSTRACT

Malignant transformation of endometriosis is rare, and most cases concern the ovaries, while extraovarian cases are mostly found in the rectovaginal septum. Incisional adenocarcinoma is extremely rare, with only few cases reported in the literature, while their molecular profile remains unknown. Thus, we report on an abdominal wall cesarean section scar endometrioid adenocarcinoma studied by next-generation sequencing and microsatellite instability analysis.


Subject(s)
Abdominal Neoplasms/pathology , Abdominal Wall/pathology , Biomarkers, Tumor/metabolism , Carcinoma, Endometrioid/pathology , Cesarean Section , Cicatrix/pathology , Postoperative Complications/pathology , Abdominal Neoplasms/diagnosis , Abdominal Neoplasms/etiology , Abdominal Neoplasms/metabolism , Carcinoma, Endometrioid/diagnosis , Carcinoma, Endometrioid/etiology , Carcinoma, Endometrioid/metabolism , Female , Humans , Immunohistochemistry , Middle Aged , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Postoperative Complications/metabolism
20.
Int J Mol Sci ; 12(6): 3409-21, 2011.
Article in English | MEDLINE | ID: mdl-21747684

ABSTRACT

OBJECTIVE: To detect the expression and clinical significances of Lewis y antigen and integrin αv, ß3 in epithelial ovarian tumors, and to explore the expression correlation between Lewis y antigen and integrin αv, ß3. METHODS: Immunohistochemical staining was performed in 95 cases of epithelial ovarian cancer, 37 cases of borderline tumors, 20 cases of benign tumors, and 20 cases of normal ovarian tissue, for the detection of Lewis y antigen and integrin αv, ß3 expressions, and to analyze the relationship between Lewis y antigen and integrin, and the relationship between clinical and pathological parameters of ovarian cancer. In addition, immunofluorescence double labeling was utilized to detect the expression correlation between Lewis y antigen and integrin αv, ß3 in ovarian cancer. RESULTS: In epithelial ovarian tumors, the expression rate of Lewis y antigen was 81.05%, significantly higher than that of borderline (51.53%) (P < 0.05) and benign (25%) (P < 0.01) tumors, and normal ovarian tissues (0) (P < 0.01). The expression rate of integrin αv, ß3 in malignant epithelial ovarian tumors was 78.95% and 82.11%, respectively, significantly higher than that of the borderline (45.94%, 40.54%) (both P < 0.05), benign group (10.00%, 15.00%) (both P < 0.01) and normal ovary group (5%, 15%) (both P < 0.01). CONCLUSIONS: Lewis y and integrins αv, ß3 are relevant to pelvic and abdominal diffusion and metastasis of ovarian cancer cells, suggesting that these two molecules mediate a boosting function for tumor metastasis.


Subject(s)
Integrin alphaVbeta3/metabolism , Lewis Blood Group Antigens/metabolism , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/pathology , Abdominal Neoplasms/metabolism , Abdominal Neoplasms/pathology , Abdominal Neoplasms/secondary , Adult , Aged , Carcinoma, Ovarian Epithelial , Female , Fluorescent Dyes/chemistry , Humans , Immunohistochemistry , Middle Aged , Neoplasm Staging , Neoplasms, Glandular and Epithelial/metabolism , Ovarian Neoplasms/metabolism
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